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PURPOSE: Multiple Endocrine Neoplasia (MEN) is a group of familial cancer syndromes that encompasses several types of endocrine tumors differentiated by genetic mutations in RET, MEN1 and CDKN1B genes. Accurate diagnosis of MEN subtypes can thus be performed through genetic testing. However, MEN variants remain largely understudied in Indian populations. Additionally, few dedicated resources to understand these disorders currently exist. METHODS: Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification. RESULTS: We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb. CONCLUSION: Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.
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BACKGROUND: Advances in Next Generation Sequencing have made rapid variant discovery and detection widely accessible. To facilitate a better understanding of the nature of these variants, American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG-AMP) have issued a set of guidelines for variant classification. However, given the vast number of variants associated with any disorder, it is impossible to manually apply these guidelines to all known variants. Machine learning methodologies offer a rapid way to classify large numbers of variants, as well as variants of uncertain significance as either pathogenic or benign. Here we classify ATP7B genetic variants by employing ML and AI algorithms trained on our well-annotated WilsonGen dataset. METHODS: We have trained and validated two algorithms: TabNet and XGBoost on a high-confidence dataset of manually annotated, ACMG & AMP classified variants of the ATP7B gene associated with Wilson's Disease. RESULTS: Using an independent validation dataset of ACMG & AMP classified variants, as well as a patient set of functionally validated variants, we showed how both algorithms perform and can be used to classify large numbers of variants in clinical as well as research settings. CONCLUSION: We have created a ready to deploy tool, that can classify variants linked with Wilson's disease as pathogenic or benign, which can be utilized by both clinicians and researchers to better understand the disease through the nature of genetic variants associated with it.
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ATPasas Transportadoras de Cobre , Aprendizaje Profundo , Variación Genética , Degeneración Hepatolenticular , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/patología , Humanos , ATPasas Transportadoras de Cobre/genética , Algoritmos , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21-22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.
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Enfermedad de Alzheimer , MicroARNs , Enfermedades Mitocondriales , Enfermedades Neurodegenerativas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Regulación de la Expresión Génica , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedades Mitocondriales/metabolismoRESUMEN
Esophageal cancer is one of the most common cancers in North East India. The molecular mechanisms of esophageal cancer susceptibility in North East India have not been fully understood. There is a need for identification of biomarkers to identify people at risk of esophageal cancer. p16 is an essential G1 cell cycle regulatory gene whose loss of function is associated with carcinogenesis. Therefore, we conducted this study to determine the prevalence of p16 gene methylation in patients with esophageal cancer to assess the feasibility of using gene methylation as a biomarker. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age, sex, and ethnicity-matched controls were included in this study. Methylation-specific PCR was used to determine the p16 methylation status. Aberrant promoter methylation of the p16 gene was detected in 81 of 100 (81%) esophageal cancer cases. Hypermethylation of p16 gene was found to be influenced by lifestyle factors. Betel quid and tobacco chewing habit synergistically with p16 methylation elevated the risk for esophageal cancer development (adjusted odds ratio (OR) = 6.88, 95% confidence interval (CI) = 1.64-28.81, p = 0.003 for betel quid chewing and adjusted OR = 7.02, 95% CI = 1.87-26.38, p = 0.001 for tobacco chewing). Further, intake of green leafy vegetables and fruits lowered the risk of esophageal cancer (adjusted OR = 0.16, 95 % CI = 0.04-0.58, p = 0.05 for green leafy vegetables and adjusted OR = 0.15, 95% CI = 0.04-0.64, p = 0.01 for fruits). Thus, p16 hypermethylation may aid as a biomarker in identifying habitués at greater risk for esophageal cancer susceptibility in high incidence region of North East India.
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Biomarcadores de Tumor/genética , Metilación de ADN , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Genes p16 , Adulto , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Esofágicas/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , India/epidemiología , Masculino , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Promoter hypermethylation is a common event in human cancer. O6-methylguanine-DNA methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancers. We aimed to explore the methylation status of MGMT gene among the North Eastern population where esophageal cancer incidence and exposure to carcinogens like nitrosamines is high. MATERIALS AND METHODS: A total of 100 newly diagnosed esophageal cancer cases along with equal number of age, sex and ethnicity matched controls were included in this study. Methylation specific PCR was used to determine the MGMT methylation status in serum samples. RESULTS: Aberrant promoter methylation of the MGMT gene was detected in 70% of esophageal cancer cases. Hypermethylation of MGMT gene was found to be influenced by environmental factors like betel quid and tobacco which contain potent carcinogens like nitrosamines. Tobacco chewing and tobacco smoking habit synergistically with MGMT methylation elevated the risk for esophageal cancer development [adjusted OR=5.02, 95% CI=1.35-18.74; p=0.010 for tobacco chewing and Adjusted OR=3.00, 95% CI=1.22-7.36; p=0.014 for tobacco smoking]. CONCLUSIONS: Results suggest that the DNA hypermethylation of MGMT is an important mechanism for MGMT gene silencing resulting in esophageal cancer development and is influenced by the environmental factors. Thus MGMT hypermethylation can be used as a biomarker for esophageal cancer in high incidence region of North East India.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Neoplasias Esofágicas/genética , Regiones Promotoras Genéticas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Metilasas de Modificación del ADN/sangre , Enzimas Reparadoras del ADN/sangre , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , India , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo , Proteínas Supresoras de Tumor/sangreRESUMEN
BACKGROUND: A case-control study was conducted to evaluate the effect of household exposure, dietary habits, smoking and Glutathione S-Transferases M1, T1 polymorphisms on lung cancer among women in Mizoram, India. MATERIALS AND METHODS: We selected 230 newly diagnosed primary lung cases and 460 controls from women in Mizoram. Multivariate logistic regression analysis was performed to estimate adjusted odds ratio (OR). RESULTS: Exposure of cooking oil fumes (p<0.003), wood as heating source for cooking (p=0.004), kitchen inside living room (p=0.001), improper ventilated house (p=0.003), roasting of soda in kitchen (p=0.001), current smokers of tobacco (p=0.043), intake of smoked fish (p=0.006), smoked meat (p=0.001), Soda (p<0.001) and GSTM1 null genotype (p=0.003) were significantly associated with increased risk of lung cancer among women in Mizoram. Significantly protective effect was observed for intake of bamboo shoots (p=<0.001) and egg (p<0.001). A clear increase in dose response gradient was observed for total cooking dish years. Risk for lung cancer tends to increase with collegial effect of indoor environmental sources (p=0.022). Significant correlation was also observed for interaction of GST polymorphisms with some of dietary habits. CONCLUSIONS: We confirmed the important role of exposure of cooking oil emission and wood smoke, intake of smoked meat, smoked fish and soda (an alkali preparation used as food additives in Mizoram) and tobacco consumption for increase risk of lung cancer among Women in Mizoram.
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Contaminación del Aire Interior/efectos adversos , Exposición a Riesgos Ambientales , Conducta Alimentaria , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Estudios de Casos y Controles , Culinaria , Femenino , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Humanos , India , Persona de Mediana Edad , Polimorfismo Genético , Factores de Riesgo , Sasa/metabolismo , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
BACKGROUND: This study aimed to explore the role of XRCC1 (Arg399Gln) and XPD (Lys751Gln) gene polymorphisms, lifestyle and environmental factors as well as their possible interactions in propensity to develop lung cancer in a population with high incidence from North East India. MATERIALS AND METHODS: A total of 272 lung cancer cases and 544 controls were collected and XRCC1 (Arg399Gln) and XPD (Lys751Gln) genotypes were analyzed using a polymerase chain reaction based restriction fragment length polymorphism assay. Conditional multiple logistic regression analysis was used to calculate adjusted odds ratios and 95% confidence intervals after adjusting for confounding factors. RESULTS: The combined Gln/Gln genotype of XRCC1 and XPD genes (OR=2.78, CI=1.05-7.38; p=0.040) was significantly associated with increased risk for lung cancer. Interaction of XRCC1Gln/Gln genotype with exposure of wood combustion (OR=2.56, CI=1.16-5.66; p=0.020), exposure of cooking oil fumes (OR=3.45, CI=1.39-8.58; p=0.008) and tobacco smoking (OR=2.54, CI=1.21-5.32; p=0.014) and interaction of XPD with betel quid chewing (OR=2.31, CI=1.23-4.32; p=0.009) and tobacco smoking (OR=2.13, CI=1.12-4.05; p=0.022) were found to be significantly associated with increased risk for lung cancer. CONCLUSIONS: Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smoking and betel quid chewing on lung cancer risk in the study population.
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Pueblo Asiatico/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ambiente , Femenino , Genotipo , Humanos , Incidencia , India , Estilo de Vida , Masculino , Persona de Mediana Edad , Factores de Riesgo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Adulto JovenRESUMEN
BACKGROUND: A very high incidence of lung cancer is observed in Mizoram and Manipur, North East India. We conducted a population based case control study to establish associations of p53 codon 72 polymorphisms and interactions with environmental factors for this high incidence. MATERIAL AND METHODS: A total of 272 lung cancer cases and 544 controls matched for age (±5 years), sex and ethnicity were collected and p53 codon 72 polymorphism genotypes were analyzed using a polymerase chain based restriction fragment length polymorphism assay. We used conditional multiple logistic regression analysis to calculate adjusted odds ratios and 95% confidence intervals after adjusting for confounding factors. RESULTS: p53 Pro/Pro genotype was significantly associated with increased risk of lung cancer in the study population (adjusted OR=2.14, CI=1.35-3.38, p=0.001). Interactions of the p53 Pro/Pro genotype with exposure to wood smoke (adjusted OR=3.60, CI=1.85-6.98, p<0.001) and cooking oil fumes (adjusted OR=3.27, CI=1.55-6.87, p=0.002), betel quid chewing (adjusted OR=3.85, CI=1.96- 7.55, p<0.001), tobacco smoking (adjusted OR=4.42, CI=2.27-8.63, p<0.001) and alcohol consumption (adjusted OR=3.31, CI=1.10-10.03, p=0.034) were significant regarding the increased risk of lung cancer in the study population. CONCLUSIONS: The present study provided preliminary evidence that a p53 codon 72 polymorphism may effect lung cancer risk in the study population, interacting synergistically with environmental factors.
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Codón/genética , Ambiente , Neoplasias Pulmonares/etiología , Polimorfismo Genético/genética , Proteína p53 Supresora de Tumor/genética , Consumo de Bebidas Alcohólicas/efectos adversos , Areca/efectos adversos , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Incidencia , India/epidemiología , Neoplasias Pulmonares/epidemiología , Masculino , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Factores de Riesgo , Fumar/efectos adversosRESUMEN
BACKGROUND: Association of angiotensin converting enzyme (ACE) gene polymorphisms with lung cancer susceptibility remains uncertain and varies with ethnicity. Northeast India represents a geographically, culturally, and ethnically isolated population. The area reports an especially high rate of tobacco usage in a variety of ways of consumption, compared with the rest of the Indian population. MATERIALS AND METHODS: We conducted a population based case control study in two major high risk region for lung cancer from Northeast India. A total of 151 consecutive lung cancer cases diagnosed histopathologically and equal numbers of controls were recruited with record of relevant sociodemographic information. Blood samples were collected and processed to identify ACE gene polymorphism. RESULTS: Significantly higher (40.4 % vs 29.1%, OR=1.97, CI=1.04-3.72; p=0.037) prevalence of the ACE II genotype was observed among lung cancer cases. Smoking was significantly associated with increased risk of lung cancer (OR=1.70, CI=1.02-2.81; p=0.041). An enhanced risk was also observed for interaction of ACE II genotype with tobacco smoking (OR=4.09, CI=1.51-11.05; p=0.005) and chewing (OR=3.68, CI=1.22-11.13; p=0.021). CONCLUSIONS: The present study indicates significant association s of the ACE II genotype with lung cancer in high risk Northeast India.